A Cdk8 inhibitor
MSC2530818 is an orally bioavailable cyclin-dependent kinase 8 (Cdk8) inhibitor (IC50 = 2.6 nM).1 It is selective for Cdk8 over a panel of 264 kinases at 1 ?M but does inhibit glycogen synthase kinase 3α (GSK3α; IC50 = 691 nM). MSC2530818 inhibits STAT1 phosphorylation in SW620 colorectal cancer cells with an IC50 value of 8 nM. It also inhibits Wnt-dependent transcription in LS 174T, COLO 205, and PA-1 cancer cells (IC50s = 32, 9, and 52 nM, respectively, in luciferase reporter assays). MSC2530818 (50 and 100 mg/kg) reduces tumor growth in a SW620 mouse xenograft model.
1.Czodrowski, P., Mallinger, A., Wienke, D., et al.Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screeningJ. Med. Chem.59(20)9337-9349(2016)
Animal experiment: | Mice: MSC2530818 is then assessed in an established SW620 human colorectal cancer xenograft model in female NCr athymic mice. Tumor-bearing mice are treated orally with MSC2530818 (50 mg/kg bid or 100 mg/kg qd) for 16 days. Tumor weights are measured and body weights are monitored[1]. |
参考文献: [1]. Czodrowski P, et al. Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening. J Med Chem. 2016 Oct 27;59(20):9337-9349. | |
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